New Adamantane Derivatives with Sigma Affinity and Antiproliferative Activity

Abstract

The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6-diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs.

Investigational sigma-1 receptor antagonists for the treatment of pain

“…The group of the University of Athens (Greece) reported the highly lipophilic adamantanyl derivatives 11 and 12, with moderate/low subtype selectivity and notable analgesic effect in the formalin test in mice sensitized by administration of paclitaxel 2 weeks before [67,68], supporting a potential role of s 1 R antagonists in chemotherapy-induced pain. M62431 (13), the only reported s 1 R ligand with zwitterionic character, was described in a poster communication [69] to show analgesic activity in a rat nerve ligation model, but little is known about its selectivity profile or any other properties.…”

Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity

“…Their antiproliferative activity against numerous cancer cell lines (colon, prostate, breast, ovarian, central nervous system, leukemia, pancreas, liver) was significant. These results in conjunction with their affinity for site 2 of the Na + channels imply that the adamantane phenylalkylamines VIII , IX and X have the pharmacological profile of mixed σ1/σ2R ligands [ 136 , 137 , 138 , 139 ].…”

“…Various adamantane derivatives present σR binding affinity not related to antiproliferative or anticancer activity [ 125 , 131 , 132 , 133 , 134 , 135 ]. However, the following adamantane phenylalkylamines VIII , IX and X , as illustrated in Figure 10 , exhibit σR binding affinity in combination with antiproliferative and anticancer activity [ 136 , 137 , 138 , 139 , 140 ].…”

“…1-Methyl-4-{4-[α-(1-adamantyl) phenylmethyl]phenyl}piperazine ( 12 ) (σ1Ki = 3.2 nM, σ2Ki = 32 nM, σ1/σ2Ki = 11.8) was prominent in pancreas [ 137 ]. 4-[4,4-Diphenyl-4-(1-adamantyl)butyl]-1-methylpiperazine ( 14 ) (σ1Ki = 15 nM, σ2Ki = 60 nM, σ1/σ2Ki = 4) displays selective action against ovarian cancer on mice (IGROV-1) and presented as potent as cisplatin [ 138 ]. The above adamantane adducts were also tested with a prototypical study (formaline test) of their effect in putative neuropathic pain induced by anticancer drug Paclitaxel [ 28 , 29 , 30 ] and proved to be putative analgesic agents.…”

Synthesis and Evaluation of Nifurtimox–Adamantane Adducts with Trypanocidal Activity

“…[5] This has led the World Health Organization (WHO) to coordinate public sector and private partnerships as part of ag lobale ffort to develop new ands afer dugs. [6] We have been interested in adamantane chemistry [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] and have prepared al arge number of analogues in an attemptt o exploit adamantane's role in bioactivity.W ep repared as eries of adamantane carbohydrazones [22] and showedt hat these derivatives are very potent trypanocidals. [6] We have been interested in adamantane chemistry [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] and have prepared al arge number of analogues in an attemptt o exploit adamantane's role in bioactivity.W ep repared as eries of adamantane carbohydrazones [22] and showedt hat these derivatives are very potent trypanocidals.…”